This project investigates three PD gene products, alpha-synuclein, UCH-L1 and DJ-1. The approach used is primarily that of in vitro biochemistry. The initial goal in each case is to understand the molecular basis for the effects of PD mutations or polymorphisms. Once a working hypothesis has been generated, we will design high-throughput assays that will allow us to identify drug-like molecules that reverse the effect of the mutation. These assays will be executed in core A. Finally, the working hypothesis will be tested by treating Parkinsonian Drosophila with drug-like molecules (via core B). The long-term (5 year) goal of this project is to confirm the relevance of particular targets for the treatment of PD and, possibly, to develop lead compounds for the development of new PD therapeutics.